Bis-tetrahydroisoquinoline derivatives: Structure analysis of the three stereoisomers of 1,1′-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline)

Elasaad, Kossay; Norberg, Bernadette; Graulich, Amaury; Liégeois, Jean-François

doi:10.1016/j.ejmech.2010.03.020

Cited by 5 publications

(3 citation statements)

References 11 publications

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“…This phenomenon of rotational isomerism has been observed earlier for non-carboxylated THIQ derivatives. 48–52 Considering the medicinal importance of the carboxylated THIQ derivatives being studied, we decided to investigate this phenomenon in detail so as to aid development of appropriate computational protocols for the interaction of THIQ3CA with proteins. Derivatives 32 and 35 were chosen as representative THIQ3CA analogs.…”

Section: Resultsmentioning

confidence: 99%

Electronically rich N-substituted tetrahydroisoquinoline 3-carboxylic acid esters: concise synthesis and conformational studies

Al‐Horani

Desai

2012

Tetrahedron

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Recent work in our laboratory has shown that the highly substituted, electronically rich 1,2,3,4–tetrahydroisoquinoline–3–carboxylic acid (THIQ3CA) scaffold is a key building block for a novel class of promising anticoagulants (Al-Horani et al. J. Med. Chem. 2011, 54, 6125–6138). The synthesis of THIQ3CA analogs, especially containing specific, electronically rich substituents, has been a challenge and essentially no efficient methods have been reported in the literature. We describe three complementary, glycine donor-based strategies for high yielding synthesis of highly substituted, electronically rich THIQ3CA esters. Three glycine donors studied herein include hydantoin 1, (±)-Boc-α-phosphonoglycine trimethyl ester 2 and (±)-Z-α-phosphonoglycine trimethyl ester 3. Although the synthesis of THIQ3CA analogs could be achieved using either of the three, an optimal, high yielding approach for the desired THIQ3CA esters was best achieved using 3 in three mild, efficient steps. Using this approach, a focused library of advanced N-arylacyl, N-arylalkyl, and bis-THIQ3CA analogs was synthesized. Variable temperature and solvent-dependent NMR chemical shift studies indicated the presence of two major conformational rotamers in 3:1 proportion for N–arylacyl–THIQ3CA analogs, which were separated by a high kinetic barrier of ~17 kcal/mol. In contrast, N–arylalkyl and bis–THIQ3CA variants displayed no rotamerism, which implicates restricted rotation around the amide bond as the origin for high-barrier conformational interconversion. This phenomenon is of major significance because structure-based drug design typically utilizes only one conformation. Overall, the work presents fundamental studies on the synthesis and conformational properties of highly substituted, electronically rich THIQ3CA analogs.

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Section: Resultsmentioning

confidence: 99%

Electronically rich N-substituted tetrahydroisoquinoline 3-carboxylic acid esters: concise synthesis and conformational studies

Al‐Horani

Desai

2012

Tetrahedron

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“…Resolution of these mixtures and characterization of the corresponding stereoisomers [6] are necessary before further biological evaluation as previously reported for AG525E1 [3,5]. More recently, a new series of 8-isopropyl analogues was prepared (Scheme 1) [1].…”

Section: Introductionmentioning

confidence: 97%

“…1 H NMR spectrum of m-xylyl isoquinolinium analogue. The sample is dissolved in DMSO-d6 . The insert shows the signal corresponding to the CH 3 of the isopropyl group of the propyl analogue for comparison.…”

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confidence: 99%

Structural analysis of some bis-(8-isopropyl-isoquinolinium) derivatives reveals a preferential folded conformation leading to a stereoselective attack by sodium borohydride

Dilly¹,

Badarau²,

Dufour³

et al. 2014

Journal of Molecular Structure

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Synthesis and radioligand binding studies of bis-(8-isopropyl-isoquinolinium) derivatives as ligands for apamin-sensitive sites on cloned SK2 and SK3 channels

Badarau

Dilly

Dufour

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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Bis-tetrahydroisoquinoline derivatives: Structure analysis of the three stereoisomers of 1,1′-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline)

Cited by 5 publications

References 11 publications

Electronically rich N-substituted tetrahydroisoquinoline 3-carboxylic acid esters: concise synthesis and conformational studies

Electronically rich N-substituted tetrahydroisoquinoline 3-carboxylic acid esters: concise synthesis and conformational studies

Structural analysis of some bis-(8-isopropyl-isoquinolinium) derivatives reveals a preferential folded conformation leading to a stereoselective attack by sodium borohydride

Synthesis and radioligand binding studies of bis-(8-isopropyl-isoquinolinium) derivatives as ligands for apamin-sensitive sites on cloned SK2 and SK3 channels

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